The long range objective of this research is to identify biochemical mechanisms of teratogenicity. In particular, this grant will focus on the actions of a series of alkylating agents that produce embryotoxic effects. Exposure to toxic alkylating agents occurs through the ingestion of preserved meats, use of cosmetics, drugs, agricultural chemicals and cigarettes. Although 10 percent of all birth defects in man have environmental causes (drugs, environmental chemicals, etc.), over 68 percent of all human birth defects have an unknown etiology. It is possible that exposure to alkylating agents may be responsible for a portion of these human birth defects of unknown etiology. The research proposed in this grant is designed to test the following hypothesis: The embryotoxicity of a series of alkylating agents can be predicted on the basis of their chemical properties. Using the rat embryo culture system, the specific questions listed below will be addressed. How does teratogenicity correlate with the following chemical parameters: ethyl versus methyl alkylation? First order versus 2nd order nucleophilic substitution reactions? Alkylation versus carbamylation? The embryotoxic/teratogenic effects that we will examine in the embryo culture system include 1) embryo lethality, 2) embryo malformations, 3) growth retardation and 4) alterations in the state of differentiation. Radioactively labelled alkylating agents will be used in the culture system to ascertain which biochemical alterations in the embryo correlate with its teratogenicity. The aim of these studies is to 1) identify common chemical properties of alkylating agents which correlate with their teratogenic efficacy and 2) identify biochemical alterations within the embryo which are critical cellular alterations leading to an embryotoxic effect.